Gastric cancer is among the malignancies with highest morbidity worldwide. Most patients with gastric cancer die of metastasis or relapse, leading to high mortality of the disease. Compared with other organs, the stomach tissue contains relatively abundant lymphatic structures, contributing to the relapse and metastasis of gastric cancer via the lymphatic system. The lymphatic system is rich in immune components, proper activation of immune cells can reduce the probability of relapse and metastasis through killing tumor cells. However, tumor cells often escape from the lysis of immune cells, the mechanisms of which are not completely clear. Therefore it is of significant clinical value to design, on the basis of the tumor immune evasion mechanisms, effective immunotherapeutic strategies, which have become another efficient anti-cancer treatment after surgery.
Human immune system can be divided into innate and adaptive components. The adaptive immunity functions through B and T lymphocytes and serves as a secondary response towards specific antigen but usually takes effect after a period of time. Contrary to it, the innate immunity, including natural killer cells (NK cells), is the first line to defense tumor cells and pathogen. NK cells can react and exert cytotoxicity within 4 hours in vitro and in vivo, via release of perforins, NK cytotoxic factors, and tumor necrosis factors. NK cells have been found to lyse tumor cells in a short amount of time, thus recent emphasis has been made on the development and clinical utilization of NK immunity to treat tumor.
The cytotoxic activity mediated by NK cells is intricately regulated by the balance between activating signals and suppressive signals. The proteins of HLA-A, B, and C (i.e., the classic HLA class I molecules) expressed on target cells interact with inhibitory receptors on NK cells and cause anergy. On the other hand, IL-2 and IL-12 secreted by dendritic cells activate NK cells.
Various remedial practices were devised based on the regulation mechanisms in order to achieve tumor regression by altering the suppressed status of NK cells, the most renowned ones including using allogenic NK cells and disrupting the inhibitory receptors on NK surface. These practices significantly enhanced the anti-cancer effects of NK-related immune therapies, but they also gave rise to auto-immune symptoms. Therefore, it remains one of the plausible means of enhancing the outcome of NK therapies to remold the cancer cells.